Massively parallel sequencing in Leber amaurosis
Massively parallel sequencing (MPS) continues to prove its worth in both the research and, increasingly, the clinical arena. This month we’re happy to bring you a report from Ghent and Brussels, Belgium, in which MPS was employed for early molecular diagnosis in patients with Leber congenital amaurosis (LCA). Like many of the hereditary eye diseases, LCA is highly genetically heterogeneous with at least 16 mutated genes thus far described. Defining the mutation responsible for LCA in any given patient is challenging and has taken on new urgency because of recent progress in gene therapy that requires knowledge of the responsible mutation.
Coppieters et al. designed an assay for multiplex sequencing of all 236 exons from 16 known LCA genes. They deployed their assay in 17 LCA patients without previously identified mutations; the causal genetic defect and a single heterozygous mutation were identified in 3 and 5 of the patients, respectively. Such assays will probably soon become the standard of care for diagnosis of genetically heterogeneous disorders. I suspect that eye diseases will be in the forefront of such applications given their heterogeneity and the recent exciting progress in gene therapy, which provides added impetus. —James P. Evans, Editor-in-Chief
Array analysis complements DNA sequencing for mutation detection
The advent of massively parallel sequencing promises to transform the ability to detect disease-causing mutations in clinical practice. However, in our enthusiasm to embrace this powerful new technology, we must not forget that some classes of mutations are transparent to many sequencing strategies. For example, most exon-sized deletions will go undetected by whole-exome sequencing, and even in the context of whole-genome sequencing, deletions can go undetected without proper informatics processing. Until now there has not been a systematic assessment of the frequency of exonic deletions and duplications for most Mendelian disorders. To address this need, Aradhya et al. designed a comparative genomic hybridization (CGH) test to probe exons in 219 genes associated with known genetic disorders. The investigators tested 3,018 individuals who had been referred for genetic testing. The exon array identified 98 partial or whole-gene deletions and two duplications, for an overall detection rate of 3.3%. Of 138 individuals tested for recessive disorders, 10.1% had an intragenic deletion, and of 313 tested for X-linked disorders, 3.5% carried a deletion or duplication. Limitations of the study included a 169-bp minimum size for deletion detection and an array design that did not include promoters. Nonetheless, these data suggest that CGH testing should routinely supplement sequence analysis for Mendelian disorders. —Karyn Hede, News Editor
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Coppieters, F., De Wilde, B., Lefever, S. et al. In This Issue. Genet Med 14, 563 (2012). https://doi.org/10.1038/gim.2012.55